Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDA-MB-231: relationship to lipid peroxidation.
Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti-cancer drugs. In this study, we examined whether lipid peroxidation is a potential mechanism through which fatty acids enhance drug cytotoxicity. We measured cell viability in the human breast cancer cell line MDA-MB-231 exposed to doxorubicin in the presence of non-cytotoxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids tested, docosahexaenoic acid (DHA, 22:6n-3) was the most potent in increasing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10(-7) M doxorubicin alone to 21% when cells were incubated with doxorubicin and DHA. After addition of an oxidant system (sodium ascorbate/2-methyl-1,4-naphthoquinone) to cells incubated with doxorubicin and DHA, cell viability further decreased to 12%. Cell hydroperoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid peroxidation inhibitor (dl-alpha-tocopherol) or when oleic acid (a non-peroxidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low peroxidation-generating potential. Thus, DHA may increase the efficacy of oxyradical-producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents.
Germain
E
E
Unité de Recherche Associée Université-INRA, Faculté de Médecine, Tours, France.
Chajès
V
V
Cognault
S
S
Lhuillery
C
C
Bougnoux
P
P
D001943:Breast Neoplasms / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage*; D004357:Drug Synergism; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D005231:Fatty Acids, Unsaturated; D008054:Lipid Peroxides; D016877:Oxidants; D004281:Docosahexaenoic Acids; D004317:Doxorubicin